N-pyridyl-1,4,5,8-tetrahydro-4a,8a-naphthalenedicarboximides



United States Patent 3,546,238 N-PYRIDYL-1,4,5,8-TETRAHYDRO-4a,8a-NAPHTHALENEDICARBOXIMIDES Eugene R. Wagner, Ziousville, Ind., assiguorto The Dow Chemical Company, Midland, Mich., a corporation of DelawareNo Drawing. Filed May 24, 1968, Ser. No. 731,744 Int. Cl. C07d 31/36,31/44 US. Cl. 260-295 4 Claims DESCRIPTION OF THE PRIOR ART Thecompounds of the present invention can be prepared by the reaction of anamine such as an aminopyridine, aniline, toluidine, xylidene or ahaloaniline with 1,4,5 ,8-tetrahydro-4a,Sa-naphthalene dicarboxylic acidanhydride in methods analogous to those described by Wagner and Rudzik,Journal of Medicinal Chemistry, 10 607 (1967).

The l,4,5,8-tetrahydro-4a,Sa-naphthalene dicarboxylic acid anhydrideemployed as a starting material herein can be prepared by methodsanalogous to those of Alder et al., Berichte, 71B, 2199 (1938) or Briglet al., Berichte, 71B, 2280 (1938). For example, a mixture of acetylenedicarboxylic acid, dioxane and butadiene is heated in a bomb at 170 C.for 20 hours. The mixture is cooled and evaporated in vacuo, theevaporation residue crystallizing on standing. The residue is mixed withwarm carbon tetrachloride and filtered, the l,4,5,8-tetrahydro-4a,8a-naphthalene dicarboxylic acid filter cake being reserved. Thefiltrate is diluted with additional carbon tetrachloride until aprecipitate forms. The filtrate is again filtered and the resultingfiltrate is cooled and evaporated in vacuo to precipitate a crystallinesolid. The solid is recrystallized from carbon tetrachloride to obtain1,4,5,8- tetrahydro-4a,8a-naphthalene dicarboxylic acid anhydride. The1,4,5 ,8-tetrahydro-4a,Sa-naphthalene dicarboxylic acid filter cakeobtained in the first filtration can be converted to the anhydride bytreatment with refluxing acetyl chloride.

SUMMARY OF THE INVENTION This invention is concerned with novelsubstitutednaphthalenedicarboximides and is particularly directed toN-substituted-l,4,5,8-tetrahydro 4a,8a naphthalenedicarboximides whereinthe substituent is pyridyl, phenyl, monohalophenyl, tolyl or xylyl. Suchcompounds correspond to the formula wherein R represents pyridyl,phenyl, monohalophenyl, tolyl or xylyl. In the present specification andclaims, the term halo is employed to designate fluoro, chloro and icebromo. The novel substituted-naphthalenedicarboximides are crystallinesolids which are soluble in organic solvents such as ethanol, benzeneand acetone and only slightly soluble in water.

The novel compounds are useful for administration to laboratory animalsin studying the behavior thereof and in studying drug effects on thecentral and peripheral nervous system. They are particularly useful ascentral nervous system depressants and for administration to animals forpotentiation of barbiturates and as sedatives. The compounds wherein Ris pyridyl, chlorophenyl or bromophenyl are particularly potentdepressants and are preferred compounds for central nervous systemdepressant use. The compounds also have herbicidal activity and for suchuses, a preferred compound is N-(2-pyridyl 1,4,5,8-tetrahydro-4a,8a-naphthalenedicarboximide.

The substituted-naphthalenedicarboximides of the invention can beprepared by the reaction of l,4,5,8-tetrahydro-4a,8a-naphthalenedicarboxylic acid anhydride with an amine which can be an aminopyridine,aniline, a haloaniline, a toluidine or a xylidene. Representative amineswhich can be employed as starting materials include 2-, 3- and4-aminopyridine, aniline, 2-, 3- and 4-brornoaniline, 0-, mandp-toluidine and 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5 -xylidene. Thereaction proceeds when the reactants are contacted and mixed and heatedat a temperature of from about to about 250 C. and preferably from aboutto 210 C. The exact proportions of the reactants to be employed are notcritical, some of the desired product being obtained when the reactantsare combined in any proportions. However, the reaction consumes thereactants in equimolar proportions, and the use of the reactants in suchproportions is desirable, the use of an excess of the amine reactantbeing preferred. The reaction is generally complete after heating forfrom about 5 to 20 minutes at a temperature within the reactiontemperature range. The substituted-naphthalenedicarboximides can beseparated by conventional methods such as trituration of the cooledmixture with a lower alkanol, crystallization from inert organicsolvents such as methanol or ethanol and filtration or centrifugation.The product can be purified by such conventional methods asrecrystallization.

In the preparation of the substituted-naphthalenedicarboximides of theinvention, 1,4,5,8-tetrahydro-4a,8a-naphthalene dicarboxylic acidanhydride is mixed together with aniline, aminopyridine, haloaniline,toluidine or xylidene in any order or fashion. The reactants areconveniently mixed directly in the absence of a solvent. However, if itis desired to employ a solvent in mixing the starting materials, the1,4,5,8-tetrahydro 4a,8a naphthalene dicarboxylic acid anhydride canconveniently be dispersed in an inert organic solvent such as ether andthe amine added slowly to the resulting mixture. The mixture can then beseparated from the solvent by filtration or evaporation. The mixture ofreactants is then heated to a temperature within the reactiontemperature range for a short period of time, usually from about 5 toabout 20 minutes, after which the mixture is cooled. Thesubstituted-naphthalenedicarboximide product is separated bycrystallization from an inert organic solvent such as ethanol. Thecrystallization can be accomplished conveniently by taking up the cooledreaction mixture in hot ethanol and cooling the ethanol mixture, with orwithout scratching or seeding to promote crystallization. The productcan be purified by conventional methods such as recrystallization fromethanol, methanol or propanol.

DESCRIPTION OF THE HREFERRED EMBODIMENTS The following examples areillustrative of the invention but are not to be construed as limitingthe same.

3 EXAMPLE. 1

Two grams of l,4,5,8-tetrahydro-4a,'8a-naphthalene dicarboxylic acidanhydride are mixed together with two grams of 3-aminopyridine and theresulting mixture is heated in an oil bath at a temperature of 188-189C. for fifteen minutes. The reaction mixture is allowed to cool slowly.The N-(3-pyridyl)-1,4,5,8tetrahydro-4a,8anaphthalenedicarboximideproduct is crystallized from milliliters of ethanol, recrystallizedtwice from ethanol and found to melt at l16l17 C. The product is foundby analysis to have carbon, hydrogen and nitrogen contents of 73.32,5.99 and 9.99 percent, respectively, as compared With the theoreticalcontents of 72.84, 5.75 and 9.99 percent, respectively, calculated forthe named structure. The structure of the product is confirmed byinfrared spectroscopy.

EXAMPLE 2 Two grams of 4-aminopyridine are mixed with two grams of1,4,5,8-tetrahydro-4a,Sa-naphthalene dicarboxylic acid and anhydride andthe mixture is heated in an oil bath at a temperature of about 190 C.for about fifteen minutes. The reaction mixture is cooled and about 10milliliters of hot ethanol are mixed therewith. The resulting mixture iscooled whereupon a crystalline solid precipitates. Pricipitation of thesolid is increased by scratching with a glass rod. The solid isseparated by filtration and recrystallized from ethanol. TheN-(4-pyridyl)-1,4, 5,8-tetrahydro-4a,8a-naphthalenedicarboximide productis found to melt at 111l13 C. and is found by analysis to have carbon,hydrogen and nitrogen contents of 72.41, 5.90 and 10.07 percent,respectively, as compared with the theoretical contents of 72.84, 5.75and 9.99 percent, respectively, calculated for the named structure.

EXAMPLE 3 Two grams of 1,4,5,8-tetrahydro-4a,Sat-naphthalenedicarboxylic acid anhydride are mixed with two grams of 2-aminopyridineand the mixture is heated in an oil bath at a temperature of about 188C. for about fifteen minutes. The reaction mixture is cooled and about10 milliliters of hot ethanol are added thereto. The mixture is cooledand triturated whereupon a crystalline solid precipitates. The solid isseparated by filtration and recrystallized from ethanol. The N(2-pyridyl)-1,4,5,8-tetrahydro-4a,8a-naphthalenedicarboximide product isfound to melt at l36137 C. and is found by analysis to have carbon,hydrogen and nitrogen contents of 72.76, 5.81 and 10.08 percent,respectively, as compared with the theoretical contents of 72.84, 5.75and 9.99 percent, respectively, calculated for the named structure.

EXAMPLE 4 Two grams of 1,4,5,8-tetrahydro-4a,Set-naphthalenedicarboxylic acid anhydride are mixed together with two grams of4bromoaniline. The resulting mixture is heated at a temperature of about190 C. for about fifteen minutes. The reaction mixture is then cooledand mixed with 10 milliliters of hot ethanol. The resulting mixture isallower to cool to room temperature and is triturated, whereupon acrystalline solid precipitates. The precipitate is separated byfiltration and recrystallized from ethanol. The N-(4bromophenyl)-1,4,5,8-tetrahydro-4a,8a-naphthalenedicarboximide productis found to melt at 134- 135 C. and is found by analysis to havehydrogen, nitrogen and bromine contents of 4.45, 22.66 and 4.02 percent,respectively, as compared with the theoretical contents of 4.50, 22.31and 3.91 percent, respectively, calculated for the named structure.

In substantially the same procedure, the followingsubstituted-naphthalenedicarboximides are prepared.

N (3 bromophenyl) l,4,5,8 tetrahydro 4a,8anaphthalenedicarboximide, acrystalline solid having a molecular weight of 358.3, is prepared bymixing l,4,5,8 tetrahydro 4a,8a naphthalene dicarboxylic acid anhydridewith an excess of 3-bromoaniline, heating the mixture at a temperatureof about -195" C., taking the product up in ethanol and thencrystallizing the product from the ethanol mixture.

N (2 bromophenyl) 1,4,5,8 tetrahydro 4a,8anaphthalenedicarboximide,having a molecular weight of 358.3, is prepared by mixing 1,4,5,8tetrahydro 4a,8anaphthalene dicarboxylic acid anhydride with an excessof 2-bromoaniline, heating the mixture and separating the product bycrystallization from ethanol.

EXAMPLE 5 Two grams of 1,4,5,8 tetrahydro 4a,8a naphthalene dicarboxylicacid anhydride are mixed with 1.5 grams of 3-chloroaniline and themixture is heated in an oil bath at a temperature of about 189 C. forabout fifteen minutes. The reaction mixture is cooled and mixed with 10milliliters of hot ethanol. The resulting mixture is cooled slowly andtriturated and a crystalline solid precipitate forms. The precipitate isseparated by filtration and recrystallized from ethanol. The N (3chlorophenyl) 1,4,5,8 tetrahydro 4a,8a naphthalenedicarboximide productis found to melt at 148-149 C. and is found by analysis to have carbon,hydrogen, nitrogen and chlorine contents of 69.10, 5.32, 11.35 and 4.59percent, respectively, as compared with the theoretical contents of68.90, 5.14, 11.30 and 4.46 percent, respectively, calculated for thenamed structure. The structure of the named product is further confirmedby infrared and nuclear magnetic resonance spectroscopy.

In substantially the same procedure, the followingsubstituted-naphthalenedicarboximides are prepared.

N (4 chlorophenyl) l,4,5,8 tetrahydro 4a,8anaphthalenedicarboximide,having a molecular weight of 313.8 and melting at l181l9 C., is preparedby mixing l,4,5,8 tetrahydro 4a,8a naphthalene dicarboxylic acidanhydride with an excess of 4-chloroaniline and heating the mixture at atemperature of about C. for about ten minutes. The product iscrystallized from ethanol and purified by recrystallization fromethanol.

N (2 chlorophenyl) 1,4,5,8 tetrahydro 4a,8anaphthalenedicarboximide,having a molecular weight of 313.8, is prepared by mixing l,4,5,8tetrahydro 4a,8anaphthalene dicarboxylic acid anhydride with an excessof 2-chloroaniline and heating the mixture at a temperature of about 190'C. The product is crystallized from ethanol.

EXAMPLE 6 Five grams of 1,4,5,8 tetrahydro 4a,8a naphthalenedicarboxylic acid anhydride are mixed with 5 grams of 4-fluoroaniline.The resulting mixture is heated at a temperature of about 180 C. forabout fifteen minutes and then allowed to cool to room temperature. Themixture is then triturated with 15 milliliters of ethanol whereupon acrystalline precipitate forms. The precipitate is separated byfiltration and the N (4 fluorophenyl)- 1,4,5,8 tetrahydro 4a,8anaphthatlenedicarboximide product is found to melt at 122.5-123.5 C. Thestructure of the product is confirmed by infrared spectros copy.

N (2 fluorophenyl) 1,4,5,8 tetrahydro 4a,8anaphthalenedicarboximide,having a molecular weight of 330.3, is prepared by emplyoing2-fiuoroaniline in lieu of 4-fiuoroaniline in the procedure describedabove.

N (3 fluorophenyl) 1,4,5,8 tetrahydro 4a,8anaphthalenedicarboximide,melting at 133134 C., is prepared by employing 3-fluoroaniline in lieuof 4-fluoroaniline in the procedure described above.

EXAMPLE 7 Three grams of 1,4,5,8 tetrahydro 4a,8a naphthalenedicarboxylic acid anhydride are mixed well with three grams of2-toluidine and the mixture is heated to a temperature of about 188 C.and held for about ten minutes. The reaction mixture is cooled andtriturated with about milliliters of ethanol. The mixture is filteredand the filter cake is recrystallized from ethanol. The N (2 tolyl)l,4,5,8 tetrahydro 4a,8a naphthalenedicarboximide product is found tomelt at 164 165 C.

In substantially the same procedure, the followingsubstituted-naphthalenedicarboximides are prepared.

N (3 tolyl) l,4,5,8 tetrahydro 4a,8a naphthalenedicarboximide, meltingat 164165 C., is prepared by mixing 1,4,5 ,8 tetrahydro 4a,8anaphthalene dicarboxylic acid anhydride with an excess of 3-toluidineand heating the mixture at a temperature of about 190 C.

N (4 tolyl) 1,4,5,8 tetrahydro 4a,8a naphthalenedicarboximide, meltingat 124-125 C., is prepared by mixing 1,4,8tetrahydro 4a,8a naphthalenedicarboxylic acid anhydride with an excess of 4-toluidine and heatingthe mixture at a temperature of about 185 C.

EXAMPLE 8 Two grams of 1,4,5,8 tetrahydro 4a,8a naphthalene dicarboxylicacid anhydride are mixed with two grams of 3,4 xylidene and the mixtureis heated in an oil bath at a temperature of about 190 C. for aboutfifteen minutes. The reaction mixture is cooled and about 15 millilitersof hot ethanol are added thereto. A crystalline solid precipitates oncooling the mixture. The solid is separated by filtration andrecrystallized from ethanol. The N (3,4 xylyl) 1,4,5,8 tetrahydro 4a,8anaphthalenedicarboximide product is found to melt at 158- 159 C.

In substantially the same procedure, the followingsubstituted-naphthalenedicarboxirnides are prepared.

N phenyl 1,4,5,8 tetrahydro 4a,8a naphthalenedicarboximide, melting at130132 C., is prepared by employing aniline in lieu of 3,4-xylidene inthe procedure described above.

N (2,4 xylyl) l,4,5,8 tetrahydro 4a,8a naphthalenedicarboximide, meltingat l58l59 C., is prepared by employing 2,4-xylidene in lieu of3,4-xylidene in the procedure described above.

N (2,5 xylyl) 1,4,5,8 tetrahydro 4a,8a naphthalenedicarboxirnide, havinga molecular weight of 307.3, is prepared by employing 2,5-xylidene inlieu of 3,4-xylidene in the procedure described above.

The compounds of the invention can be employed to control the growth ofplants, or they can be administered to animals in the study of thebehavior thereof and in the study of drug effects on the central andperipheral nervous system thereof. The compounds are typicallyadministered to animals in a depressant amount and at dosages from about50 milligrams per kilogram of animal body weight to about 250 milligramsper kilogram of animal body weight. Higher or lower dosages can also beemployed, depending upon the particular compound employed and upon suchfactors as age, species, size and physical condition of the animal,route of administration and the effect desired. Thesubstituted-naphthalenedicarboximide compounds can be administeredorally in the form of tablets, capsules, elixirs, syrups, emulsions,dispersible powders and the like, or by injection in the form of sterileinjectable suspensions or solutions. When the compounds of the inventionare employed as depressants or as plant growth control agents, they areadvantageously combined with one or more additaments or adjuvants.Useful compositions comprise one or more compounds of the invention andone or more additaments including inert diluents, solvents, dispersingagents, emulsifying agents, wetting agents, suspending agents and thelike. When the composition is administered to animals, carriers whichare pharmaceutically acceptable are employed.

In representative operations, the compounds of the invention, whenemployed as depressants in mice with barbiturates such as hexobarbital,give excellent increases in sleep time. In such operations, the mice areadministered the compounds intraperitoneally at a dosage of 215milligrams per kilogram of body weight one hour prior to theintraperitoneal administration of hexobarbital at a dosage of milligramsper kilogram. In such operations, mice administered one ofN-(4-pyridyl)- 1,4,5,8-tetrahydro 4a,8a naphthalenedicarboximide andN-(4-bromophenyl) 1,4,5,8 tetrahydro-4a,8anaphthalenedicarboximide havesleep times 6.9 and 2.4 times as great, respectively, as similar checkmice receiving only hexobarbital. In additional operations thedepressant activity upon the central nervious system is illustrated bythe reinduction of sleep following the normal period of sleep induced inmice by the intraperitoneal administration of hexobarbital at a dosageof 100 milligrams per kilogram. In such representative operations,N-(2-pyridyl) 1,4,5,8 tetrahydro 4a,8a naphthalenedicarboximide andN-(3-chlorophenyl)-l,4,5,8-tetrahydro-4a,8a-naphthalenedicarboximide'give excellent reinduction of sleep when administered intraperitoneallyimmediately subsequent to the hexobarbital-induced sleep period atintraperitoneal dosages of 60 milligrams per kilogram.

The compounds of the invention are also employed for the control ofplants. In representative operations, complete controls and kills ofpigweed are obtained when a liquid composition containingN-(2-pyridyl)-1,4,5,8- tetrahydro-4a,8a-naphthalenedicarboximide as thesole toxicant is applied as a soil drench at a dosage rate of 50 poundsof toxicant per acre to soil seeded with variable seeds of pigweed, andthe soil is thereafter held under conditions conducive to plant growth.

What is claimed is:

1. A compound selected from the group consisting of a 1,4,5,8-tetrahydro4a,8a-naphthalenedicarboximide compound corresponding to the formulaUNITED STATES PATENTS 8/1969 Wagner et al 424274 OTHER REFERENCES Wagneret al.: Journal of Medicinal Chemistry, vol. 10 (4), pp. 607-611, July1967.

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

